Adhesive transdermal formulations of diclofenac sodium

ABSTRACT

An adhesive, transdermal formulation containing a suspension of diclofenac sodium in polyoxyl hydrogenated castor oil, a copolymer of aminoalkyl methacrylate and methacrylate, one or more crosslinking agents for the copolymer, an adhesion system and possibly other excipients.

The present invention concerns adhesive, transdermal formulations ofdiclofenac sodium and adhesive patches containing such formulations.

BACKGROUND OF THE INVENTION

There are numerous known transdermal formulations in the form ofadhesive patches able to release active ingredients of various kinds.This route of administration is particularly indicated for nonsteroidanti-inflammatory drugs, especially when prolonged treatments inspecific areas of the body are required. Transdermal administrationreduces the risk of side effects of such drugs, especially at agastrointestinal level.

Diclofenac is one of the most commonly used nonsteroid anti-inflammatorydrugs because of its marked pharmacological activity.

Transdermal formulations of diclofenac, particularly of its sodium salt,are described, for example, in patents No. EP 524582, EP 582727, U.S.Pat. No. 6,193,996, EP 209975, JP 6056660, WO 99/03461, U.S. Pat. No.4,999,379 and EP 965626.

Some of the formulations described have been developed and are availableon the market.

Most of the known adhesive formulations involve the solubilisation ofthe salt of diclofenac in solvent systems such as alcobols, water,glycols or mixtures of the same.

One disadvantage of such formulations lies in the fact that the activeingredient may be unevenly distributed because of possibleprecipitations of the drug due to seeds that may be present in theformulations and/or to uneven granulometry of the drug itself before itssolution.

It has now been found that it is possible to formulate diclofenac sodiumin an adhesive, transdermal composition by resorting to a suspension ofthe drug in polyoxyl hydrogenated castor oil. The use of a suspensionovercomes the problems of stability and lack of homogeneity faced by theknown formulations, while guaranteeing at least as much bioavailability,if not more.

DESCRIPTION OF THE INVENTION

The subject of the present invention is an adhesive, transdermalformulation containing a suspension of diclofenac sodium in polyoxylhydrogenated castor oil, a copolymer of aminoalkyl methacrylate andmethacrylate, one or more crosslinking agents for said copolymer, anadhesion system and possibly other excipients.

The invention also concerns a skin patch constituted by a tissue onwhich the formulation is distributed and a protective layer.

DETAILED DESCRIPTION OF THE INVENTION

The adhesive formulation according to the invention is characterised bythe fact that the active ingredient is suspended in polyoxylhydrogenated castor oil (see European Pharmacopoeia, 1997:1083), whichis present at a percentage of between 5 and 50% of the totalformulation, preferably between 10 and 30%.

The structural polymer that constitutes the matrix of the adhesiveformulation of the invention is a cationic copolymer of a C₁-C₄ alkylester of methacrylic acid with an ester of methacrylic acid with a C₁-C₄alcohol containing a secondary or tertiary amino group, with a meanmolecular weight of between about 80,000 and about 500,000, preferablybetween about 100,000 and about 300,000.

In particular, a copolymer based on dimethylamino ethylmethacrylate andneutral esters of methacrylic acid, such as methyl, ethyl and butylesters, is preferred.

Said copolymers are available on the market under the trademarks“Eudragit E 100”, “Eudragit E112.5”, “Plastoid E 35L, M or H”. Thestructural copolymer may typically constitute between approximately 10and 30% in weight of the total adhesive formulation after drying,preferably between 12 and 25%.

Suitable crosslinking agents for the cationic copolymer are representedby polycarboxylic acids, in particular di- or tri-carboxylic acids suchas succinic acid, adipic acid and fatty acids such as lauric acid ormixtures of the same.

The crosslinking agents may be present at percentages of between 1 and20% in weight, again of the total weight of the adhesive formulationafter drying.

The formulations of the invention may also contain agents such as anacidifiers/buffers, preservatives, flexibilizers.

The use of glycerine as a flexibilizer and citric acid as an acidifieris particularly preferred.

Finally, the formulation is completed with a suitable adhesive agent,preferably constituted by a copolymer of methacrylic acid with a C1-C4ester of acrylic acid.

The adhesive formulations of the invention are prepared by mixing water,the crosslinking agents and the cationic copolymer. The mixture isheated to 70-80° C., agitated for a few hours, then cooled to 55-65° C.after which the flexibilizer is added.

Then, at the same temperature, a mixture of diclofenac sodium, polyoxylhydrogenated castor oil, acidifier and water is added.

It is agitated, cooled and the adhesive polymer is added.

The formulation thus obtained is agitated, the pH adjusted to a value ofbetween about 6 and 7, then it is spread on a suitable support, such assilicon paper, so as to give a quantity of diclofenac sodium of about 1mg/cm².

It is then dried in a current of air at a temperature of between 40 and120° C., and the support is applied to a suitable material, such as 100%non-woven polyester. The patch thus obtained is then packaged in asachet that is impermeable to gas and liquids.

Hereafter are some examples of quantitative compositions of someformulations according to the invention, expressed as percentages inweight. Examples of formulations A B C D Diclofenac sodium 17.7 17.717.7 17.7 Acrylic copolymers 32.9 33.1 37.3 42.1 Carboxylic acids 12.56.0 15.7 10.7 Glycerol 30° Bé 8.3 6.8 6.4 11.6 Citric acid 7.8 7.8 7.77.0 Polyoxyl hydrogenated castor oil 20.8 28.6 15.2 10.9

1. An adhesive, transdermal formulation containing a suspension ofdiclofenac sodium in polyoxyl hydrogenated castor oil, a cationiccopolymer of a C₁-C₄ alkyl ester of methacrylic acid with an ester ofmethacrylic acid with a C₁-C₄ alcohol containing a secondary or tertiaryamino group, one or more crosslinking agents for said copolymer, anadhesive system and, optionally, other excipients.
 2. A formulationaccording to claim 1 wherein the crosslinking agents are chosen frompolycarboxylic acids and long-chain acids.
 3. A formulation according toclaim 2 wherein the crosslinking agents are chosen from adipic acid,lauric acid, succinic acid.
 4. A formulation according to claim 1,containing also acidifying/buffering agents, preservatives,flexibilizers.
 5. A formulation according to claim 4 containing glycerinas a flexibilizer.
 6. A formulation according to claim 4 containingcitric acid as an acidifier.
 7. A formulation according to claim 1,containing between 5 and 50% in weight of polyoxyl hydrogenated castoroil.
 8. A formulation according to claim 1 containing between 10 and 30%of polyoxyl hydrogenated castor oil.
 9. A formulation according to claim1, wherein the cationic copolymer is a copolymer based on dimethylaminoethylmethacrylate and neutral esters of methacrylic acid.
 10. Aformulation according to claim 1 wherein the adhesive system isconstituted by a copolymer of methacrylic acid with a C₁-C₄ ester ofacrylic acid.
 11. A transdermal patch constituted by a tissue on which aformulation according to claim 1 is spread and by a protective layer.12. A transdermal patch according to claim 11 wherein the tissue is 100%non-woven polyester and the protective layer is silicon paper.
 13. Atransdermal patch according to claim 11, containing 1 mg of diclofenacsodium per cm² of patch.
 14. A transdermal patch according to claim 12,containing 1 mg of diclofenac sodium per cm² of patch.